title: SOX10 mutations in patients with Waardenburg-Hirschsprung disease.
abstract: Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused by defective function of the embryonic neural crest. WS and HSCR are associated in patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom (Dominant megacolon), piebald-lethal (sl) and lethal spotting (ls). The sl and ls phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively. The identification of Sox10 as the gene mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role of its human homologue SOX10 in neural crest defects. Here we show that patients from four families with WS4 have mutations in SOX10, whereas no mutation could be detected in patients with HSCR alone. These mutations are likely to result in haploinsufficiency of the SOX10 product. Our findings further define the locus heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of SOX10 in the development of two neural crest-derived human cell lineages.
authors.affiliation: INSERM U468, Hôpital Henri Mondor, Creteil, France.
authors.forename: V
authors.initials: V
authors.lastname: Pingault
authors.forename: N
authors.initials: N
authors.lastname: Bondurand
authors.forename: K
authors.initials: K
authors.lastname: Kuhlbrodt
authors.forename: D E
authors.initials: DE
authors.lastname: Goerich
authors.forename: M O
authors.initials: MO
authors.lastname: Préhu
authors.forename: A
authors.initials: A
authors.lastname: Puliti
authors.forename: B
authors.initials: B
authors.lastname: Herbarth
authors.forename: I
authors.initials: I
authors.lastname: Hermans-Borgmeyer
authors.forename: E
authors.initials: E
authors.lastname: Legius
authors.forename: G
authors.initials: G
authors.lastname: Matthijs
authors.forename: J
authors.initials: J
authors.lastname: Amiel
authors.forename: S
authors.initials: S
authors.lastname: Lyonnet
authors.forename: I
authors.initials: I
authors.lastname: Ceccherini
authors.forename: G
authors.initials: G
authors.lastname: Romeo
authors.forename: J C
authors.initials: JC
authors.lastname: Smith
authors.forename: A P
authors.initials: AP
authors.lastname: Read
authors.forename: M
authors.initials: M
authors.lastname: Wegner
authors.forename: M
authors.initials: M
authors.lastname: Goossens
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006609:High Mobility Group Proteins / Q000737:chemistry / Q000235:genetics*; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D051381:Rats; D055757:SOXE Transcription Factors; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; C527925:Sox10 protein, rat; D014157:Transcription Factors